Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammation of joints that results in erosion of articular cartilage and subchondral bone. Although current treatments with biological agents, including TNF and IL-1 inhibitors, have shown promise to improve certain arthritis-associated pathologies, no therapy has been effective in reversing disease progression. Dendritic cells (DC) are professional antigen presenting cells able to stimulate or suppress the immune response, depending upon their state of maturation. We and others have shown that immature DC as well as DC genetically modified to express IL-4 or FasL are able to reverse established murine collagen induced arthritis for extended periods of time following a single systemic administration. Similarly, injection of DC-IL-4 into NOD mice with established insulitis delayed the onset of hyperglycemia in the mouse model of diabetes. DC-derived exosomes, which are small endocytic-derived vesicles 40-100 nM in size, also have been shown to be able to regulate the immune response in an antigen-dependent manner. Recently we have demonstrated that exosomes derived from immature DC as well as from DC genetically modified to express IL-4 or FasL are able to prevent an antigen specific delayed-type hypersensitivity (DTH) response at both the site of injection as well as at distant untreated sites. In addition, our preliminary results demonstrate that exosomes derived from immunosuppressive DC are able reverse established murine arthritis following a single systemic injection as well as delay the onset of hyperglycemia in NOD mice. These results suggest that DC and, in particular, exosomes derived from DC, are able to suppress or reverse two different murine models of autoimmune diseases for extended periods of time following a single administration. Thus the goal of this proposal is to characterize, optimize and compare the immunosuppressive effects conferred by DC and DC-derived exosomes both in cell culture and in murine DTH and arthritis models. In addition, a second goal of the proposal is to examine and compare the mechanisms through which injection of DC and DC-derived exosomes suppress the immune response to specific antigens. The successful completion of the proposed aims should lead to novel and effective approaches to reverse established arthritis as well as possibly other autoimmune diseases using DC and DC-derived exosomes.